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Scripps scientists find calcium channel blockers help normalize lysosomal storage disease cells
Date:2/4/2008

And this approach to therapy is not effective at treating neurological complications of lysosomal storage diseases because injected enzymes cannot enter the brain. Because diltiazem crosses the blood-brain barrier, the drug could prove to be particularly effective in the treatment of such conditions as neuropathic Gaucher disease, which generally attacks infants and results in severe brain damage.

In addition to acting on neuropathic Gaucher disease, diltiazem and verapamil also partially restored lysosomal enzyme homeostasis in cell lines derived from patients suffering from two other distinct lysosomal storage diseases, namely -mannosidosis and type IIIA mucopolysaccharidosis. People with -mannosidosis have an inability to degrade glycoproteins, leading to intellectual disability, hearing loss, frequent infections, and other complications. People with type IIIA mucopolysaccharidosis have a deficiency in one of the enzymes needed to break down heparan sulfate, which leads to progressive central nervous system degeneration. No effective therapy is currently available for either disease.

"We found that these two compounds, diltiazem and verapamil, likely act through a calcium ion mediated increase in the concentration and distribution of cytoplasmic and endoplasmic reticulum chaperones, possibly by activating certain pathways that sense and correct protein malfolding," said Research Associate Ting-Wei Mu, the first author of the study. "Increasing calcium levelsXaltering calcium homeostasisXin the endoplasmic reticulum appears to be a relatively safe and selective strategy to partially restore mutant lysosomal enzyme homeostasis."

Altering calcium homeostasis in the endoplasmic reticulum does not appear to affect the folding efficiency of other cellular enzymes, the study reveals.

"If we can learn how to successfully manipulate calcium homeostasis, it's possible that these types of drugs might be useful for treating other pro
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Contact: Keith McKeown
kmckeown@scripps.edu
858-784-8134
Scripps Research Institute
Source:Eurekalert

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